The membrane-embedded γ-secretase complex carries out hydrolysis within the lipid bilayer in proteolyzing nearly 100 different membrane protein substrates. Among these substrates, the amyloid precursor protein (APP) has been the most studied, as generation of aggregation-prone amyloid β-peptide (Aβ) is a defining feature of Alzheimer’s disease (AD). Mutations in APP and in presenilin, the catalytic component of γ-secretase, cause familial AD, strong evidence for a pathogenic role of Aβ. However, in human trials γ-secretase inhibitors not only failed to slow AD progression, they worsened cognitive function. More in-depth study of γ-secretase and how AD-causing mutations alter its structure and function is clearly needed. Substrate-based chemical probes have been critical to unraveling the complexity of γ-secretase. Such synthetic peptides and peptidomimetics will be reviewed here, including recently reported structural and functional probes.

中文翻译：

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基于基质的阿尔茨海默氏病γ-分泌酶化学探针

膜包埋的γ-分泌酶复合物在脂质双层中进行水解，从而水解近100种不同的膜蛋白底物。在这些底物中，对淀粉样前体蛋白（APP）的研究最为深入，因为易于聚集的淀粉样β肽（Aβ）的产生是阿尔茨海默氏病（AD）的定义特征。APP和早老素（γ-分泌酶的催化成分）中的突变引起家族性AD，这是Aβ致病作用的有力证据。然而，在人体试验中，γ-分泌酶抑制剂不仅未能减缓AD进展，而且使认知功能恶化。显然需要更深入地研究γ-分泌酶以及引起AD的突变如何改变其结构和功能。基于底物的化学探针对于揭示γ-分泌酶的复杂性至关重要。